Methods for concomitant administration of colchicine and a second active agent

ABSTRACT

Methods for concomitant administration of colchicine together with one or more second active agents, e.g., ketoconazole and ritonavir, are disclosed. Such methods reduce the dangers commonly associated with such concomitant administration and provide additional benefits. Methods of notifying health care practitioners and patients regarding appropriate dosing for concomitant administration of colchicine together with second active agents are also provided.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. patent application Ser. No.12/372,046, filed Feb. 17, 2009, which is a Nonprovisional of U.S.Provisional Application Ser. Nos. 61/138,141 filed Dec. 17, 2008 and61/152,067 filed Feb. 12, 2009, all of which are hereby incorporated byreference in their entirety.

FIELD OF THE DISCLOSURE

This disclosure relates to methods allowing for the co-administration ofcolchicine together with one or more second active agents fortherapeutic purposes with improved safety compared to prior methods ofadministration.

BACKGROUND

Colchicine, chemical name (−)-N-[(7S,12aS)-1,2,3,10-tetramethoxy-9-oxo-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl]-acetamide,is an alkaloid found in extracts of Colchicum autumnale, Gloriosasuperba, and other plants. It is a microtubule-disrupting agent used inthe treatment of gout and other conditions that may be treated, relievedor prevented with anti-inflammatory treatment. Colchicine impairs themotility of granulocytes and can prevent the inflammatory phenomena thatinitiate an attack (or flare) of gout. Colchicine also inhibits mitosis,resulting in effects in cells with high turnover rates such as those inthe gastrointestinal tract and bone marrow. The primary adverse sideeffects of colchicine therapy include gastrointestinal upset such asdiarrhea and nausea.

Colchicine has a narrow therapeutic index. The margin between aneffective dose and a toxic dose of colchicine is much narrower than thatof many other widely used drugs. Consequently, actions that result inincreased colchicine levels in patients receiving colchicine therapy areparticularly dangerous. Co-administration of colchicine to patientsalong with certain other drugs can have the effect of increasingcolchicine levels. Such drug-drug interactions with colchicine have beenreported to result in serious morbid complications and, in some cases,death.

Colchicine is rapidly absorbed from the gastrointestinal tract. Peakconcentrations occur in 0.5 to 2 hours. The drug and its metabolites aredistributed in leukocytes, kidneys, liver, spleen and the intestinaltract. Colchicine is metabolized in the liver and excreted primarily inthe feces with 10 to 20% eliminated unchanged in the urine.

Gout (or gouty arthritis) is a disease caused by a build up of uric acidin the joints. Such a build up is typically due to an overproduction ofuric acid, or to a reduced ability of the kidney to excrete uric acid.Gout is characterized by excruciating, sudden, unexpected, burning pain,as well as by swelling, redness, warmness, and stiffness in the affectedjoint. Low-grade fever may also be present. A gout flare is a suddenattack of pain in affected joints, especially in the lower extremities,and most commonly in the big toe. In afflicted individuals, thefrequency of gout flares typically increases over time. In this manner,gout progresses from acute gout to chronic gout, which involves repeatedepisodes of joint pain.

Colchicine can reduce pain in attacks of acute gout flares and also canbe used beneficially for treating adults for prophylaxis of gout flares.Although its exact mode of action in the relief of gout is notcompletely understood, colchicine is known to decrease the inflammatoryresponse to urate crystal deposition by inhibiting migration ofleukocytes, to interfere with urate deposition by decreasing lactic acidproduction by leukocytes, to interfere with kinin formation and todiminish phagocytosis and subsequent inflammatory responses.

Cytochrome p450 (CYP) enzymes are agents of drug metabolism that arefound in the liver, the gastrointestinal tract and other locations inthe body. CYP enzymes occur in a variety of closely related proteinsreferred to as isozymes and different CYP isozymes may preferentiallymetabolize different drugs. The 3A family of CYP isozymes, particularlyCYP3A4, is also known to be involved in many clinically significantdrug-drug interactions, including those involving colchicine and secondactive agents. While drugs are often targets of CYP-mediated metabolism,some may also alter the expression and activity of such enzymes, thusimpacting the metabolism of other drugs. The biotransformation ofcolchicine in human liver microsomes involves formation of3-demethylchochicine and 2-demethylcolchicine. As shown by experimentsusing antibodies against CYP3A4 and experiments using chemicalinhibition of CYP3A4, this transformation is correlated with (and thusapparently mediated by) CYP3A4 activity.

P-glycoprotein (P-gp) is an ATP-dependent cell surface transportermolecule that acts as an ATPase efflux pump for multiple cytotoxicagents, including colchicine. P-gp actively pumps certain compounds,including drugs such as colchicine, out of cells. P-gp is encoded by theAdenosine triphosphate-binding cassette subfamily B member 1 (ABCB1)gene, also referred to as the multiple drug resistance 1 gene (MDR1).

Since colchicine acts intracellularly, the combined effects of CYP3A4inhibition and P-gp inhibition by second active agents that alsointeract with CYP3A4 and P-gp can cause colchicine toxicity in patientstaking what would be a safe dose of colchicine in the absence ofconcomitant second agent administration. Various studies of adversereactions from exposure to multiple drugs have found that 6.5-23% of theadverse reactions result from drug-drug interactions. Unfortunately,each year a number of deaths occur as the direct result of patientsadding a concomitant prescription pharmaceutical product to theirexisting medication regimen.

There accordingly remains a need for improved methods for administeringcolchicine to individuals who are concomitantly being treated withsecond active agents so as to reduce the possibility of colchicinetoxicity while maintaining the sometimes life-saving advantages of beingable to administer the two (or more) agents concomitantly. The presentdisclosure addresses this need and provides further advantages.

SUMMARY

In one embodiment, a method of treating an individual in need oftreatment with colchicine comprises concomitantly administering to theindividual colchicine and another drug, for example, ketoconazole orritonavir or cyclosporine, wherein the colchicine is administered as adosing regimen with a starting colchicine dose of no more than about 0.6mg colchicine, followed by either: no additional colchicine doses withinabout 12, 24, 48, or 72 hours, or at least one additional colchicinedose within about 12 hours and no more frequently than once every hourwherein each additional colchicine dose is no greater than about 0.6 mg.According to another embodiment, the other drug is, for example,verapamil or diltiazem, and the starting colchicine dose duringcoadministration with the other drug is no more than about 1.2 mgcolchicine, followed by either: no additional colchicine doses withinabout 12, 24, 48, or 72 hours, or at least one additional colchicinedose within about 12 hours.

In another aspect, a method of using colchicine comprises increasing theblood plasma levels of colchicine in a individual being administereddoses of about 0.6 mg or less of colchicine to treat acolchicine-treatable condition, said method comprising the concomitantdosing of the individual with a sufficient amount of ketoconazole toincrease the C_(max) of colchicine by about 90%, or to increase theAUC_(0-t) of colchicine in the individual by about 190%, or to increasethe AUC_(0-inf) of colchicine in the individual by about 205%, or todecrease the clearance of colchicine by about 70%, compared to theC_(max), AUC_(0-t), AUC_(0-inf), or clearance in a matched individualnot administered concomitant ketoconazole.

In yet another aspect, a method of using colchicine comprises increasingthe blood plasma levels of colchicine in an individual beingadministered doses of about 0.6 mg or less of colchicine to treat acolchicine-treatable condition, said method comprising the concomitantdosing of the individual with a sufficient amount of ritonavir toincrease the C_(max) of colchicine by about 170%, or to increase theAUC_(0-t) of colchicine in the individual by about 245%, or to decreasethe clearance of colchicine by about 70%, compared to the C_(max),AUC_(0-t), or clearance in a matched individual not administeredconcomitant ritonavir.

In another embodiment, a method for using colchicine comprises apharmacy receiving a prescription for colchicine for a patient who isconcomitantly being treated with ketoconazole or ritonavir or verapamil,and the pharmacy dispensing colchicine in response to receipt of theprescription, wherein the dispensing is preceded by: entering, into afirst computer readable storage medium in functional communication witha computer, of a unique patient identifier for said patient and at leastone drug identifier for colchicine linked to the patient identifier soas to indicate that colchicine is to be administered to the patient,wherein the computer has been programmed to issue a drug-druginteraction alert when the at least one drug identifier for colchicineis entered linked to the patient identifier so as to indicate thatcolchicine is to be administered to the patient and when the patientidentifier is also linked to an identifier indicating that ketoconazoleor ritonavir or verapamil is being concomitantly administered to thepatient, wherein, upon entry of the at least one drug identifier forcolchicine linked to the patient identifier, a drug-drug interactionalert is issued to one or more of a pharmacy technician, a pharmacist,or a pharmacy customer obtaining the colchicine, said alert indicatingthat that ketoconazole or ritonavir is being concomitantly administeredto the patient and that prior to the colchicine being dispensed, thecolchicine dosing regimen must be reviewed and, if necessary adjusted,so that when the colchicine is delivered to the pharmacy customerobtaining the colchicine it is delivered along with instructions for thecolchicine to be taken in accordance with a dosing regimen of no morethan about 0.6 mg colchicine, followed by either: no additionalcolchicine doses within about 12, 24, 48, or 72 hours, or at least oneadditional colchicine dose within about 12 hours and no more frequentlythan once every hour wherein each additional colchicine dose is nogreater than about 0.6 mg.

A method of treating a patient with colchicine comprises administeringan adjusted daily dosage amount of colchicine to the patient who isreceiving concomitant administration of ritonavir, wherein the adjusteddaily dosage amount of colchicine is about 25% to 50% of an intendeddaily dosage amount of colchicine, and wherein the intended daily dosageamount of colchicine is a dose suitable for the patient if the patientwere not receiving concomitant ritonavir.

A method of treating a patient with colchicine comprises administeringan adjusted daily dosage amount of colchicine to the patient who isreceiving concomitant administration of ketoconazole, wherein theadjusted daily dosage amount of colchicine is about 25% to 50% of anintended daily dosage amount of colchicine, and wherein the intendeddaily dosage amount of colchicine is a daily dosage amount suitable forthe patient if the patient were not receiving concomitant ketoconazole.

A method of treating an individual in need of treatment for gout flares,comprises concomitantly administering colchicine and azithromycin, andcarefully monitoring the individual for potential toxicity. The methodfurther comprises adjusting the dose of colchicine or azithromycin asnecessary to avoid adverse side effects.

A method of treating an individual with colchicine comprisesconcomitantly administering colchicine and verapamil, and carefullymonitoring the individual for signs and symptoms of adverse sideeffects. The method further comprises administering an adjusted dailydosage amount of colchicine to the patient who is receiving concomitantadministration of verapamil, wherein the adjusted daily dosage amount ofcolchicine is about 50% to 75% of an intended daily dosage amount ofcolchicine, and wherein the intended daily dosage amount of colchicineis a daily dosage amount suitable for a patient if the patient were notreceiving concomitant verapamil.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows mean colchicine plasma concentrations followingadministration of single and multiple oral doses of colchicine 0.6 mg inhealthy adults, N=13, Y axis=colchicine concentration, ng/mL, Xaxis=time in hours, ♦=day 1, ▪=day 25. See Example 1.

FIG. 2 shows a pharmacokinetic profile comparison of single-dosecolchicine (0.6 mg, alone) and single-dose colchicine (0.6 mg)co-administered with steady-state clarithromycin in healthy adults, Yaxis=colchicine concentration, ng/mL, X axis=time in hours, N=23,●=colchicine alone, ♦=colchicine plus clarithromycin. See Example 2.

FIG. 3 shows a pharmacokinetic profile comparison of single-dosecolchicine (0.6 mg, alone) and single-dose colchicine (0.6 mg)co-administered with steady-state clarithromycin and steady-statecyclosporine in healthy adults. Y axis=colchicine concentration, ng/mL,X axis=time in hours, N=18, ▴=colchicine alone, ●=colchicine plusclarithromycin, ▪=colchicine plus cyclosporine.

FIG. 4 shows a pharmacokinetic profile comparison of single-dosecolchicine (0.6 mg, alone) and single-dose colchicine (0.6 mg)co-administered with steady-state ketoconazole and steady-stateritonavir in healthy adults. Y axis=colchicine concentration, ng/mL, Xaxis=time in hours, N=18, ▴=colchicine alone, ●=colchicine plusketoconazole, ▪=colchicine plus ritonavir.

FIG. 5 shows a pharmacokinetic profile comparison of single-dosecolchicine (0.6 mg, alone) and single-dose colchicine (0.6 mg)co-administered with steady-state azithromycin and steady-statediltiazem in healthy adults. Y axis=colchicine concentration, ng/mL, Xaxis=time in hours, N=18, ▴=colchicine alone, ●=colchicine plusazithromycin, ▪=colchicine plus diltiazem.

These and other embodiments, advantages and features of the presentinvention become clear when detailed description is provided insubsequent sections.

DETAILED DESCRIPTION

Disclosed herein are methods for safely administering colchicineconcomitantly with a second active agent, wherein the second activeagent is a CYP3A4 inhibitor, a P-gp inhibitor, or both. Exemplary secondactive agents that are CYP3A4 and P-gp inhibitors are azithromycin,ketoconazole, ritonavir, diltiazem, verapamil and cyclosporine. It hasnow been discovered that certain reduced or limited colchicine dosageamounts, when administered with concomitantly administered recommendeddosage amounts of second active agents that are CYP3A4 inhibitors, P-gpinhibitors, or both, achieve plasma colchicine levels that aretherapeutically effective, but are not significantly higher, andtherefore not significantly more toxic, than plasma levels achieved byadministration of manufacturers' recommended colchicine dosages in theabsence of concomitant administration with the second active agent.Thus, colchicine and second active agents that are CYP3A4 inhibitors,P-gp inhibitors, or both, can be administered concomitantly withimproved safety when colchicine is administered as disclosed herein.

Without being held to theory, it has been hypothesized by the inventorsherein that P-gp inhibition is more important in the elimination ofcolchicine than CYP3A4 inhibition. The CYP3A4 and P-gp inhibitionpotential of clarithromycin, azithromycin, ketoconazole, ritonavir,diltiazem and cyclosporine are given in Table 1. Based on their level ofP-gp inhibition, it was predicted that clarithromycin and cyclosporinewill increase colchicine concentrations more than ketoconazole orritonavir, which will increase colchicine levels more than verapamil,azithromycin or diltiazem. The results presented herein confirm thishypothesis.

TABLE 1 CYP3A4 and P-gp inhibition potential of second active agentsDrug CYP3A Inhibition potential P-gp Inhibition potential Clarithromycin+++++ +++++ Cyclosporine +++++ +++++ Ketoconazole +++++ +++ Ritonavir+++++ +++ Verapamil ++ ++ Diltiazem + + Azithromycin + +

Ritonavir (Norvir®, Abbott Laboratories) is an inhibitor of HumanImmunodeficiency Virus (HIV) protease and is approved for the treatmentof HIV-infection when used as part of a highly active antiretroviraltherapy (HAART) regimen at the recommended dose of 600 mg twice daily.Although a very potent and effective protease inhibitor at therecommended dose, ritonavir is not well tolerated by HIV-infectedpatients at the approved dose and therefore, is generally not usedclinically as a sole, therapeutic protease inhibitor within a HAARTregimen. Rather, ritonavir is used more often as a pharmacokineticenhancer or ‘boosting agent’ when combined with other approved proteaseinhibitors that are CYP3A4 and P-gp substrates and also have inherentbioavailability issues, such as poor bioavailability due to first passeffect Improving the pharmacokinetic disposition of other proteaseinhibitors is possible due to the potent CYP3A4 and P-gp inhibitoryactivity ritonavir possesses. Sub-therapeutic ritonavir doses are usedto achieve pharmacokinetic enhancement of the co-administered proteaseinhibitors; typically 100 mg of ritonavir administered twice daily isthe ritonavir dose used in combination with the primary proteaseinhibitor. This low-dose ritonavir regimen boosts the bioavailability ofthe second protease inhibitor without contributing significantly to theadverse event profile of the HAART regimen.

Cyclosporine (Neoral®, Novartis Pharmaceuticals Corporation) is theactive principle in Neoral® an oral formulation that immediately forms amicroemulsion in an aqueous environment. Cyclosporine is indicated forkidney, liver, and heart transplantation; rheumatoid arthritis andpsoriasis. Cyclosporine is extensively metabolized by the CYP3A4 enzymesystem in the liver, and to a lesser degree in the gastrointestinaltract, and the kidney. The metabolism of cyclosporine can be altered bythe co-administration of a variety of agents.

Ketoconazole is a synthetic broad-spectrum antifungal agent available inscored white tablets, each containing 200 mg ketoconazole base for oraladministration. Ketoconazole tablets are indicated for the treatment ofthe following systemic fungal infections: candidiasis, chronicmucocutaneous candidiasis, oral thrush, candiduria, blastomycosis,coccidioidomycosis, histoplasmosis, chromomycosis, andparacoccidioidomycosis. Ketoconazole is a potent inhibitor of the CYP3A4enzyme system. Co-administration of ketoconazole and drugs primarilymetabolized by the CYP3A4 enzyme may result in increased plasmaconcentrations of the drugs that could increase or prolong boththerapeutic and adverse side effects.

Azithromycin is a macrolide antibiotic indicated for the treatment ofpatients with mild to moderate infections caused by susceptible strainsof the designated microorganisms in specific conditions. Azithromycinremains the sole agent developed and marketed within the azalidemacrolide subclass. Due to its dibasic structure, azithromycin hasdemonstrated unique pharmacokinetic properties that differ significantlyfrom those of classic macrolide agents. Azithromycin's pharmacokineticsare characterized by low concentrations in serum, secondary to rapid andsignificant uptake by fibroblasts and acute reactant cells such aspolymorphonuclear leukocytes (PMNs), monocytes, and lymphocytes.Azithromycin is a weak to moderate CYP3A4 inhibitor.

Diltiazem (Cardizem® CD, Biovail Pharmaceuticals, Inc. [Biovail]) is anextended-release (ER) calcium ion influx inhibitor available in bluecapsules, each containing 240 mg diltiazem hydrochloride for oraladministration. Diltiazem ER capsules are indicated for the treatment ofhypertension and the management of chronic stable angina and angina dueto coronary artery spasm. Diltiazem is a CYP3A4 and P-gp inhibitor.

Verapamil HCl ER (Mylan Pharmaceuticals, Inc.) is a calcium ion influxinhibitor available in a pale green, capsule shaped, film-coatedtablets, each containing 240 mg verapamil hydrochloride for oraladministration. Verapamil HCl ER tablets are indicated for themanagement of hypertension. Verapamil HCl ER is a potent CYP3A4 and P-gpinhibitor.

In one embodiment, colchicine is administered to an individual sufferingfrom a condition treatable with colchicine, and the concomitant secondactive agent (e.g., ketoconazole, ritonavir, cyclosporine, verapamil, ordiltiazem or any other CYP3A4 or P-gp inhibitor) is administeredconcurrently while the colchicine administration is reduced, or theindividual has recently completed a dosing regimen of the second activeagent, in which case the colchicine administration may still be reducedfor a period of time.

In one embodiment, disclosed herein is a method of administeringcolchicine and a second active agent (e.g., ketoconazole, ritonavir, orcyclosporine) wherein an individual is administered the colchicineaccording to a colchicine dosing regimen of a single starting colchicinedose of no more than about 0.6 mg colchicine, followed by either noadditional colchicine doses within about 12, 24, 48, or 72 hours, orfollowed by at least one additional colchicine dose within 12 hours andno more frequently than once every hour (e.g., every 3, 4, 6, 8, or 12hours). In this embodiment, each additional colchicine dose isspecifically no greater than about 0.3 mg and the individual is an adultindividual or a pediatric individual. Specifically, the startingcolchicine dose is about 0.6 mg or about 0.3 mg, and each additionalcolchicine dose is about 0.3 mg. In one embodiment, when additionaldoses are administered, only two, three, or four additional colchicinedoses are administered within about 24 hours. Specifically, theindividual is an adult individual and the starting colchicine dose isabout 0.6 mg, and each additional colchicine dose, if any, is about 0.3mg. In one embodiment, only three additional colchicine doses areadministered within about 24 hours.

In one embodiment, disclosed herein is a method of administeringcolchicine and a second active agent (e.g., verapamil or diltiazem)wherein an individual is administered the colchicine according to acolchicine dosing regimen of a single starting colchicine dose of nomore than about 1.2 mg colchicine, followed by either no additionalcolchicine doses within about 12, 24, 48, or 72 hours, or followed by atleast one additional colchicine dose within 12 hours and no morefrequently than once every hour (e.g., every 3, 4, 6, 8, or 12 hours).In this embodiment, each additional colchicine dose is specifically nogreater than about 0.3 mg or 0.6mg and the individual is an adultindividual or a pediatric individual. Specifically, the startingcolchicine dose is about 0.6mg or 1.2 mg, and each additional colchicinedose is about 0.3 mg or 0.6mg. In one embodiment, when additional dosesare administered, only two, three, or four additional colchicine dosesare administered within about 24 hours. Specifically, the individual isan adult individual and the starting colchicine dose is about 1.2 mg,and each additional colchicine dose, if any, is about 0.3 mg or 0.6 mg.In one embodiment, only three additional colchicine doses areadministered within about 24 hours.

In one embodiment, the second active agent is ketoconazole or ritonavir.In one embodiment, the ketoconazole is administered to the individual ata dosage of about 200 mg daily and the colchicine dosing regimen is oneabout 0.6 mg colchicine dose to start, followed by 0, 1, 2, 3, or 4additional colchicine doses of about 0.6 mg every 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, or 12 hours (e.g., every 2, 3, 4, 5, or 6 hours) after thepreceding colchicine dose. In another embodiment, the ritonavir isadministered to the individual at a dosage of about 200 to 1200 mg daily(e.g., in 2×100 mg doses or 2×600 mg doses) and the colchicine dosingregimen is one about 0.6 mg colchicine dose to start, followed by 0, 1,2, 3, or 4 additional colchicine doses of about 0.6 mg every 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, or 12 hours (e.g., every 2, 3, 4, 5, or 6 hours)after the preceding colchicine dose. In an exemplary regimen fortreatment of acute gout flares, ingestion of colchicine is continueduntil a total of no more than about 1.2, 1.4, 1.6, 1.8, 2, or 2.4 mg ofcolchicine has been ingested, after which ingestion of colchicine isstopped until a subsequent acute gout flare occurs. More preferably, thecolchicine is administered as a dosage form of 0.6 mg (e.g., one 0.6 mgcolchicine tablet), or 0.3 mg (e.g., one half of a 0.6 mg tablet) ofcolchicine and administration of the dosage form is not repeated withina period of at least about two days, preferably at least about threedays.

In one embodiment, the second active agent (e.g., ketoconazole orritonavir or cyclosporine) is administered to the individual before thecolchicine is administered to the individual, and wherein theadministration of second active agent is terminated no more than aboutfourteen days prior to the initiation of colchicine administration. Forexample, the method comprises administering colchicine to an individualalso taking a second active agent (e.g., ketoconazole or ritonavir orcyclosporine), or having completed treatment with the second activeagent within the prior 14 days, the individual being administered asingle dose of about 0.6 mg or about 0.3 mg of colchicine to treat agout flare, which administration is not repeated within any 3-dayperiod. According to this embodiment if the second active agent isinstead verapamil or diltiazem, if the second active agent is terminatedno more than about fourteen days prior to the initiation of thecolchicine administration to treat a gout flare, the single dose ofcolchicine is about 1.2mg not to be repeated within a 3-day period.

In another aspect, herein disclosed is a method for increasing the bloodplasma levels of colchicine in an individual to whom colchicine is beingadministered to treat or prevent a colchicine-responsive condition. Thismethod comprises the concomitant dosing of the individual with asufficient amount of ketoconazole to increase the C_(max) of colchicineby about 90%, or to increase the AUC_(0-t) of colchicine in theindividual by about 190%, or to increase the AUC_(0-inf) of colchicinein the individual by about 205%, or to decrease the clearance ofcolchicine by about 70%, compared to the C_(max), AUC_(0-t), orclearance in the same or a matched individual when not beingadministered a concomitant ketoconazole. In a specific embodiment, theindividual is being administered no more than hourly doses of about 0.6mg of colchicine or less, and the amount of ketoconazole is about 200mg. In one embodiment, the single dose is one 0.6 mg colchicine tablet.

In yet another aspect, herein disclosed is a method for increasing theblood plasma levels of colchicine in an individual to whom colchicine isbeing administered to treat or prevent a colchicine-responsivecondition. This method comprises the concomitant dosing of theindividual with a sufficient amount of ritonavir to increase the C_(max)of colchicine by about 170%, or to increase the AUC_(0-t) of colchicinein the individual by about 245%, or to decrease the clearance ofcolchicine by about 70%, compared to the C_(max), AUC_(0-t), orclearance in the same or a matched individual when not beingadministered concomitant ritonavir. In a specific embodiment, theindividual is being administered no more than hourly doses of about 0.6mg of colchicine or less, and the amount of ritonavir is about 200 toabout 1200 mg. In one embodiment, the single dose is one 0.6 mgcolchicine tablet.

In one embodiment, a method of treating a patient with colchicinecomprises administering an adjusted daily dosage amount of colchicine tothe patient who is receiving concomitant administration of ritonavir,wherein the adjusted daily dosage amount of colchicine is 25% to 50% ofan intended daily dosage amount of colchicine, and wherein the intendeddaily dosage amount of colchicine is a daily dosage amount suitable forthe patient if the patient were not receiving concomitant ritonavir.Treating is, for example, to prevent gout flares, to treat acute gout,or to treat familial Mediterranean fever. When the colchicine isadministered to prevent gout flares, the adjusted daily dosage amount ofcolchicine may reduced from a 0.6 mg twice daily intended dose to a 0.6mg once daily adjusted dose. Alternatively, when the colchicine isadministered to prevent gout flares, wherein the adjusted daily dosageamount of colchicine is reduced from a 0.6 mg once daily intended doseto a 0.3 mg once daily adjusted dose. In one embodiment, when treatingis for acute gout, the intended daily dosage amount is 1.8 to 2.4 mg,and the maximum adjusted daily dosage amount is 0.6 mg, not to berepeated within 3 days. In another embodiment, treating is for acutegout, the intended daily dosage amount is 2.4 to 4.8 mg and the maximumadjusted daily dosage amount is 0.6 to 1.2 mg, not to be repeated within3 days. In yet another embodiment, treating is for familialMediterranean fever and the daily dosage amount 1.2 to 2.4 mg foradults, and the maximum adjusted daily dosage amount is 0.6 mg, given,for example, in two 0.3 mg doses. In another embodiment, treating is forfamilial Mediterranean fever and the intended daily dosage amount is 0.9to 1.8 mg for children 6-12 years or 4-6 years, and the maximum adjusteddaily dosage amount is 0.6 mg, given, for example, in two 0.3 mg doses.The concomitantly administered dose of ritonavir is, for example, 200 mgper day. In one embodiment, the ritonavir is administered to the patientbefore the colchicine is administered to the patient, and wherein theadministration of ritonavir is terminated no more than about fourteendays prior to the initiation of colchicine administration. The methodoptionally further comprises carefully monitoring the individual forpotential toxicity. Any 0.3 mg dose contemplated in this method can be asingle 0.3 mg dosage form or one-half a 0.6 mg dosage form, e.g.one-half a 0.6 mg colchicine tablet.

A method of treating a patient with colchicine comprises administeringan adjusted daily dosage amount of colchicine to the patient who isreceiving concomitant administration of ketoconazole, wherein theadjusted daily dosage amount of colchicine is 25% to 50% of an intendeddaily dosage amount of colchicine, and wherein the intended daily dosageamount of colchicine is a daily dosage amount suitable for the patientif the patient were not receiving concomitant ketoconazole. Treating is,for example, to prevent gout flares, to treat acute gout, or to treatfamilial Mediterranean fever. When the colchicine is administered toprevent gout flares, the adjusted daily dosage amount of colchicine mayreduced from a 0.6 mg twice daily intended dose to a 0.6 mg once dailyadjusted dose. Alternatively, when the colchicine is administered toprevent gout flares, wherein the adjusted daily dosage amount ofcolchicine is reduced from a 0.6 mg once daily intended dose to a 0.3 mgonce daily adjusted dose. In one embodiment, when treating is for acutegout, the intended daily dosage amount is 1.8 to 2.4 mg, and the maximumadjusted daily dosage amount is 0.6 mg, not to be repeated within 3days. In another embodiment, treating is for acute gout, the intendeddaily dosage amount is 2.4 to 4.8 mg and the maximum adjusted dailydosage amount is 0.6 to 1.2 mg, not to be repeated within 3 days. In yetanother embodiment, treating is for familial Mediterranean fever and thedaily dosage amount 1.2 to 2.4 mg for adults, and the maximum adjusteddaily dosage amount is 0.6 mg, given, for example, in two 0.3 mg doses.In another embodiment, treating is for familial Mediterranean fever andthe intended daily dosage amount is 0.9 to 1.8 mg for children 6-12years or 4-6 years, and the maximum adjusted daily dosage amount is 0.6mg, given, for example, in two 0.3 mg doses. The concomitantlyadministered dose of ketoconazole is, for example, 250 mg per day. Inone embodiment, the ketoconazole is administered to the patient beforethe colchicine is administered to the patient, and wherein theadministration of ketoconazole is terminated no more than about fourteendays prior to the initiation of colchicine administration. The methodoptionally further comprises carefully monitoring the individual forpotential toxicity. Any 0.3 mg dose contemplated in this method can be asingle 0.3 mg dosage form or one-half a 0.6 mg dosage form, e.g.one-half a 0.6 mg colchicine tablet.

A method of treating a patient with colchicine comprises administeringan adjusted daily dosage amount of colchicine to the patient who isreceiving concomitant administration of cyclosporine, wherein theadjusted daily dosage amount of colchicine is 25% to 50% of an intendeddaily dosage amount of colchicine, and wherein the intended daily dosageamount of colchicine is a daily dosage amount suitable for the patientif the patient were not receiving concomitant cyclosporine. Treating is,for example, to prevent gout flares, to treat acute gout, or to treatfamilial Mediterranean fever. When the colchicine is administered toprevent gout flares, the adjusted daily dosage amount of colchicine mayreduced from a 0.6 mg twice daily intended dose to a 0.3 mg once dailyadjusted dose. Alternatively, when the colchicine is administered toprevent gout flares, wherein the adjusted daily dosage amount ofcolchicine is reduced from a 0.6 mg once daily intended dose to a 0.3 mgonce every other day adjusted dose. In one embodiment, when treating isfor acute gout, the intended daily dosage amount is 1.8 to 2.4 mg, andthe maximum adjusted daily dosage amount is 0.6 mg, not to be repeatedwithin 3 days. In another embodiment, treating is for acute gout, theintended daily dosage amount is 2.4 to 4.8 mg and the maximum adjusteddaily dosage amount is 0.6 to 1.2 mg, not to be repeated within 3 days.In yet another embodiment, treating is for familial Mediterranean feverand the daily dosage amount 1.2 to 2.4 mg for adults, and the maximumadjusted daily dosage amount is 0.6 mg, given, for example, in two 0.3mg doses. In another embodiment, treating is for familial Mediterraneanfever and the intended daily dosage amount is 0.9 to 1.8 mg for children6-12 years or 4-6 years, and the maximum adjusted daily dosage amount is0.6 mg, given, for example, in two 0.3 mg doses. The concomitantlyadministered dose of cyclosporine can be various dosage strengthsadministered per day, and can be administered as an oral preparation,topically, or intravenously. In one embodiment, the cyclosporine isadministered to the patient before the colchicine is administered to thepatient, and wherein the administration of cyclosporine is terminated nomore than about fourteen days prior to the initiation of colchicineadministration. The method optionally further comprises carefullymonitoring the individual for potential toxicity. Any 0.3 mg dosecontemplated in this method can be a single 0.3 mg dosage form orone-half a 0.6 mg dosage form, e.g. one-half a 0.6 mg colchicine tablet.

In another embodiment, colchicine is concomitantly administered withazithromycin. Concomitant administration of azithromycin with colchicineincreases exposure to colchicine approximately 46% and thus has thepotential to produce colchicine toxicity. During concomitant use ofazithromycin and colchicine, the physician should carefully monitorindividuals for any signs or symptoms of colchicine toxicity.Additionally, dosing adjustments to either the colchicine and/or theazithromycin may be necessary to avoid adverse side effects.

A method of treating a patient with colchicine comprises administeringan adjusted daily dosage amount of colchicine to the patient who isreceiving concomitant administration of verapamil, wherein the adjusteddaily dosage amount of colchicine is 50% to 75% of an intended dailydosage amount of colchicine, and wherein the intended daily dosageamount of colchicine is a daily dosage amount suitable for the patientif the patient were not receiving concomitant verapamil. Treating is,for example, to prevent gout flares, to treat acute gout, or to treatfamilial Mediterranean fever. When the colchicine is administered toprevent gout flares, the adjusted daily dosage amount of colchicine mayreduced from a 0.6 mg twice daily intended dose to a 0.3 mg once dailyadjusted dose. In one embodiment, when treating is for acute gout, theintended daily dosage amount is 1.8 to 2.4 mg, and the maximum adjusteddaily dosage amount is 1.2 mg. In another embodiment, treating is foracute gout, the intended daily dosage amount is 2.4 to 4.8 mg and themaximum adjusted daily dosage amount is about one-third the intendeddaily dosage amount. In yet another embodiment, treating is for familialMediterranean fever and the daily dosage amount 1.2 to 2.4 mg foradults, and the maximum adjusted daily dosage amount is 1.2 mg, given,for example, in two 0.6 mg doses. In one embodiment, the verapamil isadministered to the patient before the colchicine is administered to thepatient, and wherein the administration of verapamil is terminated nomore than about fourteen days prior to the initiation of colchicineadministration. The method optionally further comprises carefullymonitoring the individual for potential toxicity. Any 0.3 mg dosecontemplated in this method can be a single 0.3 mg dosage form orone-half a 0.6 mg dosage form, e.g. one-half a 0.6 mg colchicine tablet.

Disclosed herein are specific dosage reductions of colchicine thatimprove safety when colchicine is co-administered with certain activeagents. The dose of colchicine recommended for administration withoutco-administration of certain other active agents, such as CYP3A4 or P-gpinhibitors, is referred to as an intended daily dosage amount. Thereduced or modified daily dosage amount determined from the experimentspresented herein is referred to as an adjusted daily dosage amount. Anadjusted daily dosage amount is thus a daily dosage amount that can besafely co-administered with a second active agent as disclosed herein. Adose adjustment is thus a dose of colchicine and does not includecessation of colchicine, that is, a dose of 0 mg of colchicine.

In these and other embodiments, the colchicine-responsive condition isgout (e.g., a gout flare in a chronic gout sufferer), familialMediterranean fever (FMF), thrombocytopenic purpura, pericarditis,scleroderma, or Behçet's disease. In some embodiments, the treatmentwith colchicine is either palliative or prophylactic. The gout may beacute gout, e.g. a gout flare, or chronic gout.

Acute Gout

Acute gout, or gout flares, can be treated according to the followingtreatment schedule. This table indicates the original, or intended,dose, i.e., the dose of colchicine recommended absent concomitantadministration of the drugs listed below. This table also presents thedose adjustment of the present invention, or the recommended colchicinedose to be administered when the strong and moderate CYP3A4 and P-gpinhibitors are administered concomitantly with colchicine when thepatient is being treated for acute gout, or an acute gout flare.

Colchicine Dose Recommendation Original Intended Dose (Total Drug Dose)Dose Adjustment Strong CYP3A4 Regimen Reduced by Two Thirds InhibitorsErythromycin 1.2 mg (2 tablets) at the first 0.6 mg (1 tablet) × 1 dose.Ketoconazole sign of the flare followed by 0.6 mg Dose to be repeated noRitonavir (1 tablet) one hour later. earlier than 3 days. Dose to berepeated no earlier than 3 days. Moderate CYP3A4 Regimen Reduced by OneThird Inhibitors Diltiazem 1.2 mg (2 tablets) at the first 1.2 mg (2tablets) × 1 dose. Verapamil sign of the flare followed by 0.6 mg Doseto be repeated no (1 tablet) one hour later. earlier than 3 days. Doseto be repeated no earlier than 3 days. Strong P-gp Regimen Reduced byTwo Thirds Inhibitors Cyclosporine 1.2 mg (2 tablets) at the first 0.6mg (1 tablet) × 1 dose. sign of the flare followed by 0.6 mg Dose to berepeated no (1 tablet) one hour later. earlier than 3 days. Dose to berepeated no earlier than 3 days.Chronic Gout

For chronic gout, an original intended daily dosage amount is 1.2 mg or6 mg. Alternatively, an intended daily dosage amount of chronic gout canbe as much as 2.4 mg per day. The daily dosage amount for chronic goutcan be administered at one time or dosed at intervals throughout theday, e.g. twice daily, three times daily, or four times daily.

Chronic gout, with and without a concomitant dose of another drug, canbe treated according to the following treatment schedule:

Colchicine Dose Adjustment for Co-administration with Interacting DrugsIf No Alternative Available

Colchicine Dose Recommendation Drug Original Intended Dose DoseAdjustment Clarithromycin 0.6 mg twice daily 0.3 mg once daily 0.6 mgonce daily 0.3 mg once every other day Cyclosporine 0.6 mg twice daily0.3 mg once daily 0.6 mg once daily 0.3 mg once every other dayErythromycin 0.6 mg twice daily 0.3 mg once daily 0.6 mg once daily 0.3mg once every other day Ritonavir 0.6 mg twice daily 0.6 mg once daily0.6 mg once daily 0.3 mg once dailyFamilial Mediterranean Fever

Familial Mediterranean Fever (FMF) can be treated according to thefollowing intended daily dosing schedule:

Daily dosage amount Age Usual Maximum Adults and children >12 years 1.2mg 2.4 mg Children >6 to 12 years 0.9 mg 1.8 mg Children 4 to 6 years0.3 mg 1.8 mg

When colchicine is given to patients with FMF concomitantly with otherdrugs, the adjusted (reduced) dosage amount of colchicine, according tothis embodiment, is provided in the table below:

Concomitant Drug Class Noted or Anticipated or Food Outcome ClinicalComment Strong CYP3A4 Significant increase in Use colchicine withInhibitors: atazanavir, colchicine plasma levels¹; caution at reducedclarithromycin, indinavir, fatal colchicine toxicity maximum dose of 0.3mg itraconazole, has been reported with twice daily with increasedketoconazole, nefazodone, clarithromycin, a strong monitoring foradverse nelfinavir, ritonavir, CYP3A4 inhibitor. effects. In patientswith saquinavir, telithromycin Similarly, significant renal or hepaticincrease in colchicine impairment, use of plasma levels is colchicine inconjunction anticipated with other with these drugs is strong CYP3A4inhibitors. contraindicated. Moderate CYP3A4 Significant increase in Usecolchicine with inhibitors: amprenavir, colchicine plasma caution atreduced aprepitant, diltiazem, concentration is maximum dose of 0.6 mgerythromycin, fluconazole, anticipated. twice daily with increasedfosamprenavir, grapefruit Neuromuscular toxicity monitoring for adversejuice, verapamil has been reported with effects. In patients withdiltiazem and verapamil renal or hepatic interactions. impairment, use amaximum dose of 0.3 mg twice daily. Strong P-gp Inhibitors Significantincrease in Use colchicine with e.g. Cyclosporine, colchicine plasmalevels¹; caution at reduced ranolazine. fatal colchicine toxicitymaximum dose of 0.3 mg has been reported with twice daily with increasedcyclosporine, a strong P- monitoring for adverse gp inhibitor.Similarly, effects. In patients with significant increase in renal orhepatic colchicine plasma levels is impairment, use of anticipated withother colchicine in conjunction strong P-gp inhibitors. with these drugsis contraindicated.

Pharmacy management systems are computer-based systems that are widelyused by commercial pharmacies to manage prescriptions and to providepharmacy and medical personnel with warnings and guidance regardingdrugs being administered to individuals. Such systems typically providealerts warning either or both of health care providers and patients whena drug that may be harmful to the particular patient is prescribed. Forexample, such systems can provide alerts warning that a patient has anallergy to a prescribed drug, or is receiving concomitant administrationof a drug that can have a dangerous interaction with a prescribed drug.U.S. Pat. Nos. 5,758,095, 5,833,599, 5,845,255, 6,014,631, 6,067,524,6,112,182, 6,317,719, 6,356,873, and 7,072,840, each of which isincorporated herein by reference, disclose various pharmacy managementsystems and aspects thereof Many pharmacy management systems are nowcommercially available, e.g., CENTRICITY Pharmacy from BDM InformationSystems Ltd., General Electric Healthcare, Waukesha, Wis., Rx30 PharmacySystems from Transaction Data Systems, Inc., Ocoee, Fla., SPEED SCRIPTfrom Digital Simplistics, Inc., Lenexa, Ky., and various pharmacymanagement systems from OPUS-ISM, Hauppauge, N.Y.

In another aspect, herein disclosed are methods for using colchicinewhich methods involve the use of pharmacy management systems.

In one aspect, one such method comprises a pharmacy receiving aprescription for colchicine for a patient who is suffering from gout(e.g., acute gout flares or chronic gout) and who is concomitantly beingtreated with a second active agent (e.g., ketoconazole or ritonavir)that is an inhibitor of CYP3A and P-glycoprotein, followed by thepharmacy dispensing colchicine in response to receipt of theprescription, wherein the dispensing is preceded by entry into a firstcomputer readable storage medium, in functional communication with acomputer, of a unique patient identifier for said patient and at leastone drug identifier for colchicine linked to the patient identifier soas to indicate that colchicine is to be administered to the patient. Thecomputer is programmed to issue a drug-drug interaction alert when theat least one drug identifier for colchicine is entered linked to thepatient identifier so as to indicate that colchicine is to beadministered to the patient and when the patient identifier is alsolinked to an identifier indicating that a second active agent (e.g.,ketoconazole or ritonavir) that is an inhibitor of CYP3A4 orP-glycoprotein is being concomitantly administered to the patient. Uponentry of the at least one drug identifier for colchicine linked to thepatient identifier, a drug-drug interaction alert is issued to one ormore of a pharmacy technician, a pharmacist, or a pharmacy customerobtaining the colchicine, said alert indicating that a second activeagent (e.g., ketoconazole or ritonavir) is being concomitantlyadministered to the patient and that prior to the colchicine beingdispensed, the colchicine dosing regimen must be reviewed and, ifnecessary adjusted, so that when the colchicine is delivered to thepharmacy customer obtaining the colchicine it is delivered along withinstructions for the colchicine to be taken in accordance with a dosingregimen of no more than one about 0.6 mg colchicine dose to start (e.g.,following the onset of the acute gout attack or the first sign of a goutflare) followed by either: no additional colchicine doses within about12, 24, 48, or 72 hours, or at least one additional colchicine dosewithin about 12 hours and no more frequently than once every hour andwherein each additional colchicine dose is no greater than about 0.6 mg,and wherein the patient ingests the colchicine as instructed.

The drug-drug interaction alert is preferably issued as one or both of awritten warning on a display screen of the pharmacy management computersystem, and a printed warning. The printed warning may be attached to orpackaged with the dispensed prescription.

In one aspect, the identifier indicating that ketoconazole is beingconcomitantly administered to the patient is an identifier indicatingthat the second active agent is ketoconazole and is linked to at leastone further identifier indicating that the ketoconazole is prescribed sothat 200 mg of ketoconazole is to be ingested by the patient daily, inwhich case the dosing regimen for colchicine is preferably one about 0.6mg colchicine dose to start, optionally followed by additionalcolchicine doses, e.g., 0, 1, 2, 3, or 4 additional colchicine doseswithin 24 hours of about 0.3 mg ingested every 1, 2, 3, 4, 5, 6, 7, 8, 910, 11, or 12 hours (e.g., every 2, 3, 4, 5, or 6 hours) after thepreceding colchicine dose. In another embodiment, the identifierindicating that ketoconazole is being concomitantly administered to thepatient is an identifier indicating that the second active agent isketoconazole is linked to at least one further identifier, entered intoa second computer readable storage medium in functional communicationwith a computer, the second storage medium being the same as ordifferent from the first storage medium, and the further identifierindicating that the ketoconazole is prescribed so that about 200 mg ofketoconazole is to be ingested by the patient daily, in which case thecolchicine dosing regimen is one about 0.6 mg colchicine dose to start,followed by an about 0.3 mg colchicine dose ingested every 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, or 12 hours (e.g., every six to eight hours)after the preceding colchicine dose. In one embodiment, the dosingregimen calls for the about 0.3 mg colchicine dose every six to eighthours. In another embodiment, the dosing regimen calls for one dose ofthe colchicine every eight to twelve hours.

In yet another preferred aspect, the identifier indicating thatketoconazole is being concomitantly administered to the patient is anidentifier indicating that the second active agent is ketoconazole andis linked to at least one further identifier, entered into a secondcomputer readable storage medium in functional communication with acomputer, the second storage medium being the same as or different fromthe first storage medium, and the further identifier indicating that theketoconazole is prescribed so that about 200 mg of ketoconazole is to beingested by the patient daily and the dosing regimen is one about 0.3 mgcolchicine dose to start, followed by an about 0.3 mg colchicine doseingested every 2, 3, 4, 5, 6, 7, or 8 hours (e.g., every eight to twelvehours) after the preceding colchicine dose.

A preferred dosing regimen calls for ingestion of colchicine to becontinued until a total of no more than 1.2 mg or 2.4 mg of colchicinehas been ingested, after which ingestion of colchicine is to be stopped,e.g., for at least 2, 3, 4, 5, 6, or 7 days, or until a subsequent acutegout flare, or the first sign of a subsequent gout flare, occurs.

In another aspect, the identifier indicating that ritonavir is beingconcomitantly administered to the patient is an identifier indicatingthat the second active agent is ritonavir and is linked to at least onefurther identifier indicating that the ritonavir is prescribed so that200 or 1200 mg of ritonavir is to be ingested by the patient daily, inwhich case the dosing regimen for colchicine is preferably one about 0.6mg colchicine dose to start, optionally followed by additionalcolchicine doses, e.g., 0, 1, 2, 3, or 4 additional colchicine doseswithin 24 hours of about 0.3 mg ingested every 1, 2, 3, 4, 5, 6, 7, 8, 910, 11, or 12 hours (e.g., every 2, 3, 4, 5, or 6 hours) after thepreceding colchicine dose. In another embodiment, the identifierindicating that ritonavir is being concomitantly administered to thepatient is an identifier indicating that the second active agent isritonavir is linked to at least one further identifier, entered into asecond computer readable storage medium in functional communication witha computer, the second storage medium being the same as or differentfrom the first storage medium, and the further identifier indicatingthat the ritonavir is prescribed so that about 1200 mg of ritonavir isto be ingested by the patient daily, in which case the colchicine dosingregimen is one about 0.6 mg colchicine dose to start, followed by anabout 0.3 mg colchicine dose ingested every 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, or 12 hours (e.g., every six to eight hours) after the precedingcolchicine dose. In one embodiment, the dosing regimen calls for theabout 0.3 mg colchicine dose every six to eight hours. In anotherembodiment, the dosing regimen calls for one dose of the colchicineevery eight to twelve hours.

In yet another aspect, the identifier indicating that ritonavir is beingconcomitantly administered to the patient is an identifier indicatingthat the second active agent is ritonavir and is linked to at least onefurther identifier, entered into a second computer readable storagemedium in functional communication with a computer, the second storagemedium being the same as or different from the first storage medium, andthe further identifier indicating that the ritonavir is prescribed sothat about 1200 mg of ritonavir is to be ingested by the patient dailyand the dosing regimen is one about 0.3 mg colchicine dose to start,followed by an about 0.3 mg colchicine dose ingested every 2, 3, 4, 5,6, 7, or 8 hours (e.g., every eight to twelve hours) after the precedingcolchicine dose.

Also disclosed herein is a dosage adjustment method for administeringcolchicine to a patient to treat a medical condition, the patientconcomitantly treated with a second active agent. The second activeagent may be, for example, ritonavir, ketoconazole, cyclosporine,verapamil, or diltiazem. The method comprises determining a firstcolchicine dosing regimen (the colchicine dosing regimen suitable foradministration in the absence of co-administration with a second activeagent, which dosing regimen may consist of one or more doses ofcolchicine); and determining a second active agent dosing regimen; andadministering the second active agent to the patient at the secondactive agent dosing regimen while concomitantly administering colchicineto the patient according to a second colchicine dosing regimen, whichmay consist of one or more reduced colchicine doses. The secondcolchicine dosing regimen is a fraction of the first colchicine dosingregimen, where the fraction is obtained by administering reducedcolchicine doses or by reducing the frequency of colchicine doses, andwherein the fraction is less than or equal to about ⅔ or less than orequal to about ½ or less than or equal to about ⅓.

According to this embodiment, upon the administering the second activeagent to the patient at the second active agent dosing regimen whileconcomitantly administering colchicine to the patient at the secondcolchicine dosing regimen, the therapeutic circulating level ofcolchicine is achieved in the patient. Preferably, the fraction isselected from 1/12, ⅙, ¼, ⅓, 5/12, and ½, more preferably, the fractionis ⅓ or ½. In one embodiment, if the second colchicine dosing regimencomprises a “first” colchicine dose, and one or more “subsequent”colchicine doses, each subsequent colchicine dose may be the same as thefirst dose, or a fraction of the first dose. The fraction is selectedfrom about 1/12, about ⅙, about ¼, about ⅓, about 5/12, about ½, andabout 7/12, e.g., about ½ or about ⅔. In one example, the secondcolchicine dosing regimen is once-a-day, twice-a-day, three-times-a-dayor four-times-a-day. In a variation of this example, the initialtreatment day in, a second colchicine dosing regimen that lasts for morethan one day, has one more dose administered than are administered eachsubsequent day.

Preferably the second active agent is selected from ketoconazole,cyclosporine, ritonavir, verapamil, or diltiazem. The specificconditions are selected from gout, FMF, thrombocytopenic purpura, andBehçet's disease. In one embodiment, the gout is an acute gout flare andthe colchicine treatment schedule is an acute treatment schedule adaptedfor treatment of acute gout flares, or the gout is chronic gout, and thecolchicine treatment schedule is a chronic treatment schedule adaptedfor prophylaxis, or prevention, of flares. In another embodiment, thefraction of colchicine administered to the patient concomitantly with asecond active agent that is a CYP3A4 or P-gp inhibitor is ⅓ or ½ theoriginal intended amount of colchicine and treatment with colchicine isinitiated subsequent to or at the same time as initiation of treatmentwith the second active agent.

Colchicine is one of the most widely used drugs for treating familialMediterranean fever (FMF). It has been reported that 5-10% of FMFpatients do not show a beneficial response to colchicine administration.A polymorphism in the ABCB1 gene, the “ABCB1 3435 C to T polymorphism”has been reported to correlate with this lack of response to colchicinetreatment, with patients with the homozygous TT genotype exhibiting themost pronounced “non-responder” phenotypes.

Accordingly, in another aspect, provided herein is a method for treatinga patient suffering from FMF, which patient is a colchicinenon-responder. Preferably, the patient is homozygous for the TT genotypeof the ABCB1 3435 C to T polymorphism. The method entails theconcomitant administration of a P-gp inhibitor and colchicine to thepatient. Exemplary P-gp inhibitors include ketoconazole and ritonavir.Preferred dosages of the P-gp inhibitor for this purpose correspond tothose called for in the prescribing information for the drug inquestion. For ketoconazole, an exemplary dosage is 200 mg per day. Forritonavir, an exemplary dosage is 200 or 1200 mg per day. Specificcolchicine dosing regimens for this purpose are the same as used fortreatment of FMF in responders, though the doses of colchicineadministered may be increased as tolerated, e.g., up to two to threetimes the typical doses.

The following examples further illustrate aspects of this disclosure butshould not be construed as in any way limiting its scope. In particular,the conditions are merely exemplary and can be readily varied by one ofordinary skill in the art.

EXAMPLES Example 1 Pharmacokinetic Study in Healthy Adults of Single vs.Multiple Oral Doses of Colchicine Tablets

This study was a single-center, open-label, single-sequence, two-periodstudy to evaluate the pharmacokinetic profile of colchicine followingsingle and multiple oral doses of colchicine tablets, 0.6 mg, in healthyvolunteers.

In Period 1, study subjects received a 0.6-mg dose of colchicine afteran overnight fast of at least 10 hours. In Period 2, subjects received a0.6 mg dose of colchicine in the morning and the evening (approximately12 hours later) for 10 days (steady state regimen). Subjects received alight breakfast served 60 minutes following dose administration in themorning and the evening dose was administered 90 minutes after anevening meal on Days 15 through 24 only. On Day 25, the colchicine dosewas administered after an overnight fast of at least 10 hours and lunchwas served 4 hours post-dose. Study periods were separated by a 14-daywashout. Following the single dose and the last dose of the multipledose regimen (beginning on the mornings of Day 1 and Day 25,respectively), blood samples were collected (6 mL each) from eachsubject within 1 hour prior to dosing and after dose administration atstudy hours 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 (while confined)and 36, 48, 72, and 96 (on an outpatient basis). Plasma concentrationsof colchicine and its metabolites were determined using validatedLC/MS-MS methods.

Thirteen healthy, non-smoking subjects with a mean age of 25.5 years(range 19 to 38 years) and within 15% of ideal body weight were enrolledin this study. All subjects completed both dosing periods according toprotocol.

After a single dose, plasma concentrations are no longer quantifiable 24hours post-dose in all but 1 subject. After the last dose of the steadystate regimen, concentrations remained quantifiable for 48 to 72 hours.Review of individual subject data shows that no subject experienced asecondary colchicine peak, either following a single dose or uponmultiple dosing.

All 2-O-demethylcolchicine (2-DMC) concentrations were below the levelof quantitation (LOQ, 0.2 ng/mL) and only one sample from 1 subject (of13 subjects) had a detectable 3-O-demethylcolchciine (3-DMC)concentration, which was near the level of quantitation. Therefore,metabolites are not discussed further.

In healthy adults, colchicine appears to be readily absorbed when givenorally, reaching a mean maximum plasma concentration of 2.5 ng/mL in 1.5hours after a single dose. The drug is distributed widely, with anapparent volume of distribution of 540 L, greatly exceeding total bodywater. The elimination half-life as calculated following a single oraldose is approximately 5 hours. Levels were not detectable by 24 hourspost-dose and this is therefore not an accurate estimate.Pharmacokinetic parameter values are summarized in the table below.

Review of trough plasma concentrations indicates that steady state wasattained by approximately the eighth day of dosing for most subjects.Colchicine may have a diurnal variation reflected in the observed Cminconcentrations at steady state. Cmin concentrations prior to the morningdose are approximately 12% higher than the Cmin concentrations prior tothe evening dose (Day 23 and Day 24). The mean Cmin concentrationobserved on Day 25 was 0.907 ng/mL.

Colchicine accumulated following administration of multiple doses to anextent greater than expected. Exposure was nearly two-fold higher(approximately 1.7 based on AUC [Day 25 AUC_(0-τ)/Day 1 AUC_(0-∞)] andapproximately 1.5 based on Cmax [Day 25 C_(max)/Day 1 C_(max)]). Thisobservation could be attributable to an underestimation of AUC∞following a single dose. With the higher plasma levels that occur withrepeated dosing, a longer terminal elimination half life is apparent,26.6 hours. Pharmacokinetic parameter values are summarized in Tables3-5.

TABLE 3 Colchicine Pharmacokinetic Parameter Values FollowingAdministration of A Single Oral Dose of Colchicine 0.6 mg in HealthyAdults (N = 13) MEAN STDEV % CV MEDIAN MIN MAX AUC_(0-t) 10494.663544.08 33.77 10560.90 4812.88 18091.85 (pg-hr/mL) AUC_(0-inf) 12268.184422.08 36.05 11451.45 7252.66 23801.68 (pg-hr/mL) Cmax 2450.15 702.1128.66 2480.00 1584.00 3977.00 (pg/mL) Tmax 1.50 0.54 36.00 1.50 1.003.00 (hr) K_(el) 0.1829 0.0592 32.38 0.1992 0.0359 0.2443 (1/hr) T_(1/2)4.95 4.43 89.54 3.48 2.84 19.29 (hr)

TABLE 4 Colchicine Pharmacokinetic Parameter Values FollowingAdministration of Multiple (b.i.d.) Oral Doses of Colchicine 0.6 mg inHealthy Adults (N = 13) MEAN STDEV % CV MEDIAN MIN MAX AUC_(0-t)43576.96 9333.26 21.42 41925.10 29328.78 58265.35 (pg-hr/mL) AUC_(0-τ)20366.61 3322.12 16.31 20423.08 13719.18 25495.25 (pg-hr/mL) AUC_(0-inf)54198.77 9214.54 17.00 54113.43 37599.76 67944.65 (pg-hr/mL) C_(max)3553.15 843.45 23.74 3734.00 1977.00 4957.00 (pg/mL) C_(min) 906.51152.19 16.79 903.50 636.23 1149.67 (pg/mL) C_(ave) 1697.22 276.84 16.311701.92 1143.26 2124.60 (pg/mL) T_(max) 1.31 0.60 45.61 1.00 0.50 3.00(hr) K_(el) 0.0267 0.0044 16.34 0.0261 0.0206 0.0333 (1/hr) T_(1/2)26.60 4.33 16.26 26.51 20.82 33.65 (hr)

TABLE 5 Mean (% CV) Colchicine Pharmacokinetic Parameter ValuesFollowing Administration of Single and Multiple (b.i.d.) Oral Doses ofColchicine 0.6 mg in Healthy Adults Vd/F (L) CL/F (L/hr) Colchicine0.6-mg Single Dose (N = 13) Day 1 341 (54.4) 54.1 (31.0) Colchicine 0.6mg b.i.d. × 10 days Day 25 1150 (18.73) 30.3 (19.0) CL = Dose/AUC_(0-t)(Calculated from mean values) Vd = CL/Ke (Calculated from mean values)

In tables, the parameter CL/F denotes the apparent total body clearanceafter administration, calculated as Total Dose/Total AUC0-_(tau); andV_(d)/F denotes the apparent total volume of distribution afteradministration, calculated as Total Dose/(Total AUC_(∞)×K_(el)). FIG. 1shows mean colchicine plasma concentrations following administration ofsingle and multiple oral doses of colchicine 0.6 mg in healthy adults.

Example 2 Clinical Drug-Drug Interaction Study of Colchicine andClarithromycin

A single-center, open-label, one sequence, two-period study was carriedout in 23 healthy subjects. On Day 1, a single 0.6-mg dose of colchicinewas administered. After completing a 21-day washout period, all subjectsreceived 250 mg of clarithromycin administered twice daily for 7 days(Days 22 through 29), a sufficient dose and duration to inhibit CYP3A4and Pgp. On the final day (Day 29), a single dose of colchicine wasco-administered with the clarithromycin dose. When combined withsteady-state clarithromycin, there is a significant increase in exposureto colchicine as compared to when colchicine is given alone: the meanC_(max) and AUC_(0-t) concentrations increased 167% and 250%,respectively. In addition, co-administration of clarithromycin andcolchicine resulted in an increase of 233% in the plasma eliminationhalf-life (t½) of colchicine and a 75% decrease in apparent clearance(CL/F). A summary of the mean (% CV) colchicine pharmacokineticparameters for Day 1 (colchicine administered alone) and Day 29(colchicine co-administered with steady-state clarithromycin) are givenin the table below and illustrated in Table 5.

TABLE 6 Comparison of Single-Dose Colchicine (0.6 mg, Alone) andSingle-Dose Colchicine (0.6 mg) Co-Administered with Steady-StateClarithromycin in Healthy Adults Arithmetic Mean (% CV) Colchicine +Colchicine Clarithromycin Parameter (units) (N = 23) (N = 23) AUC_(0-t)(ng · hr/mL) 12.37 (37.64) 41.95 (23.31) AUC_(0-inf) (ng · hr/mL) 15.53(49.6) 52.62 (22.84) C_(max) (ng/mL) 2.84 (30.97) 8.44 (17.63) T_(max)(hr)* 1.50 (0.50-2.00) 1.00 (0.50-2.00) CL/F (L/hr) 46.8 (43.68) 12.0(23.75)

FIG. 2 shows a pharmacokinetic profile comparison of single-dosecolchicine (0.6 mg, alone) and single-dose colchicine (0.6 mg)co-administered with steady-state clarithromycin in healthy adults.Based on the foregoing data, it is concluded that the dose of colchicineco-administered with clarithromycin should be reduced by ⅔.

Example 3 Clinical Drug-Drug Interaction Study of Colchicine andCyclosporine

This study was an open-label, non-randomized, single-center,one-sequence, two-period drug interaction study conducted in healthymale and female volunteers. Twenty-four (24) non-smoking, non-obeseadult volunteers were enrolled. All subjects were dosed and studied as asingle cohort, with each subject receiving the same treatment in anon-randomized fashion.

A single dose of colchicine, 0.6 mg, was administered alone on Day 1,and then co-administered with cyclosporine on Day 15. Cyclosporine wasadministered as a single-dose (1×100 mg capsule) on the morning of Day15. A 14 day washout period was completed after the first colchicinedose on Day 1 and prior to the co-administration of colchicine andcyclosporine doses on Day 15.

Serial blood samples were collected by individual venipuncture up to 96hours following drug administration on Day 1 and Day 15. Blood samplesfor determination of colchicine plasma concentrations were obtained attime zero (pre-dose) and after dose administration at 0.5, 1.0, 1.5, 2,3, 4, 5, 6, 8, 12, and 24 hours post-dose on a confined basis. Subjectswere then return to the clinic on a non-confined basis for continuedblood sampling collection at 36, 48, 72, and 96 hours post-doseadministration on Days 2-5 (Period 1) and Days 16-19 (Period 2).Cyclosporine plasma concentrations were not measured.

TABLE 7 Comparison of Single-Dose Colchicine (0.6 mg, Alone) andSingle-Dose Colchicine (0.6 mg) Co-Administered with Steady-StateCyclosporine in Healthy Adults Arithmetic Mean (% CV) Colchicine +Colchicine Cyclosporine Parameter (units) (N = 23) (N = 23) AUC_(0-t)(ng · hr/mL) 12.55 39.83 AUC_(0-inf) (ng · hr/mL) 15.00 47.31 C_(max)(ng/mL) 2.72 8.82 T_(max) (hr)* 1.15 1.13 CL/F (L/hr) 48.24 13.42

FIG. 3 shows a pharmacokinetic profile comparison of single-dosecolchicine (0.6 mg, alone) and single-dose colchicine (0.6 mg)co-administered with steady-state clarithromycin and steady-statecyclosporine in healthy adults. Based on the foregoing data, the dose ofcolchicine co-administered with cyclosporine should be reduced byapproximately ½ to ¾.

Example 4 Clinical Drug-Drug Interaction Study of Colchicine andRitonavir

An open-label, non-randomized, single-center, one-sequence, two-perioddrug interaction study was conducted in healthy male and femalevolunteers; there will be a 14-day washout between the two periods.Twenty-four (24) non-smoking non-obese adult volunteers were enrolled.All subjects were dosed and studied as a single cohort, with eachsubject receiving the same treatment in a non-randomized fashion.

All subjects received a single 0.6-mg dose of colchicine on Day 1administered under standard fasting conditions, followed by a 14-daywashout period completed on an outpatient basis. At discharge on Day 2,study subjects were instructed to return to the clinical site on themornings and evenings of Days 15 through 18 to receive two daily dosageamounts of ritonavir (1×100 mg ritonavir capsule twice daily (every 12hours) on Days 15-18) in a ‘directly-observed’ fashion; after taking thefirst dose of ritonavir, subjects remained in the clinic for observationfor 1 hour post-dose administration on Day 15. On the evening of Day 18,study participants remained at the clinic for their final studyconfinement period. In the morning on Day 19, study subjects received asingle 0.6 mg colchicine dose with a single 100 mg ritonavir dose andstudy subjects received the final 100 mg ritonavir dose 12 hours laterin the evening on Day 19 under standard fasting conditions.

Serial blood samples were collected by individual venipuncture up to 96hours following drug administration on Day 1 and Day 19. Blood samplesfor determination of colchicine plasma concentrations were obtained attime zero (pre-dose) and after dose administration at 0.5, 1.0, 1.5, 2,3, 4, 5, 6, 8, 12, and 24 hours post-dose on an inpatient basis.Subjects returned to the clinic on an outpatient basis for continuedblood sampling collection at 36, 48, 72, and 96 hours post-doseadministration. Ritonavir plasma concentrations were not measured.

TABLE 8 Comparison of Single-Dose Colchicine (0.6 mg, Alone) andSingle-Dose Colchicine (0.6 mg) Co-Administered with Steady-StateRitonovir in Healthy Adults: In-transformed data Colchicine Colchicine +Alone Ritonovir % Ratio C_(max) (pg/mL), 1798.37 4835.39 268.88geometric mean AUC_(0-t) (pg · h/mL), 7642.71 27793.08 363.65 geometricmean AUC_(∞) (pg · h/mL), 9551.74 33771.36 353.56 geometric mean

TABLE 9 Comparison of Single-Dose Colchicine (0.6 mg, Alone) andSingle-Dose Colchicine (0.6 mg) Co-Administered with Steady-StateRitonavir in Healthy Adults Arithmetic Mean (% CV) Median (Range) forT_(max) Colchicine + Colchicine Ritonavir Alone Parameter (units) (N =18) (N = 18) AUC_(0-t) (ng · hr/mL) 29.05 (30.76) 8.41 (47.46) AUC_(0-∞)(ng · hr/mL) 35.28 (29.79) 10.41 (45.48) C_(max) (ng/mL) 4.99 (25.18)1.87 (28.19) T_(max) (hr) 1.5 (1-1.5) 1 (0.5-1.5) CL/F (L/hr) 18.59(31.58) 67.93 (39.47)

Following exposure to 100 mg b.i.d. ×5 days, there was a significantincrease in exposure to a single 0.6-mg colchicine (approximately 245%).Mean peak colchicine concentration increased by approximately 170%.Total apparent oral clearance was decreased by 70% withco-administration. T_(max) is not affected. Elimination half-life couldnot be estimated accurately as plasma concentrations were notquantifiable after 24 hours.

FIG. 4 shows a pharmacokinetic profile comparison of single-dosecolchicine (0.6 mg, alone) and single-dose colchicine (0.6 mg)co-administered with steady-state ritonavir and steady-stateketoconazole in healthy adults. Based on the foregoing data, the dose ofcolchicine co-administered with ritonavir should be reduced byapproximately ½.

Example 5 Clinical Drug-Drug Interaction Study of Colchicine andKetoconazole

This study was an open-label, non-randomized, single-center,one-sequence, two-period drug interaction study conducted in healthymale and female volunteers; there will be a 14-day washout between thetwo periods. Twenty-four (24) non-smoking, non-obese adult volunteerswere enrolled.

A single dose of colchicine, 0.6 mg, was administered alone on Day 1,and then co-administered with ketoconazole on Day 19 (AM dose).Ketoconazole was administered for 5 consecutive days [200 mg twice daily(every 12 hours)] beginning on the morning of Day 15, with the last 200mg ketoconazole dose administered on the evening on Day 19. Total studyparticipation, exclusive of up to 28 days of screening, wasapproximately 24 days, during which subjects will be confined on twooccasions for a total confinement of approximately 3 days.

Serial blood samples were collected by individual venipuncture up to 96hours following drug administration on Day 1 and Day 19. Blood samplesfor determination of colchicine plasma concentrations were obtained attime zero (pre-dose) and after dose administration at 0.5, 1.0, 1.5, 2,3, 4, 5, 6, 8, 12, and 24 hours post-dose on an inpatient basis.Subjects then returnee to the clinic on an outpatient basis forcontinued blood sampling collection at 36, 48, 72, and 96 hourspost-dose administration. Ketoconazole plasma concentrations were notmeasured.

TABLE 10 Comparison of Single-Dose Colchicine (0.6 mg, Alone) andSingle-Dose Colchicine (0.6 mg) Co-Administered with Steady-StateKetoconazole in Healthy Adults: ln-transformed data ColchicineColchicine + Alone Ketoconazole % Ratio C_(max) (pg/mL), 2598.28 5078.50195.46 geometric mean AUC_(0-t) (pg · h/mL), 11087.99 33223.80 299.64geometric mean AUC_(∞) (pg · h/mL), 13185.92 42143.00 319.61 geometricmean

TABLE 11 Comparison of Single-Dose Colchicine (0.6 mg, Alone) andSingle-Dose Colchicine (0.6 mg) Co-Administered with Steady-StateKetoconazole in Healthy Adults Arithmetic Mean (% CV) Colchicine +Colchicine Ketoconazole Parameter (units) (N = 23) (N = 23) AUC_(0-t)(pg · hr/mL) 11988.61 34382.82 AUC_(0-inf) (pg · hr/mL) 14314.0943688.90 C_(max) (pg/mL) 2779.08 5266.92 T_(max) (hr)* 1.00 1.02 CL/F(L/hr) 49301.09 14797.94 *Median (Range) for T_(max)

Following administration of ketoconazole 200 mg b.i.d. ×5 days, therewas a significant increase in exposure to a single oral dose ofcolchicine 0.6 mg (C_(max) and AUC_(0-t) increased by 90% and 190%,respectively, and AUC_(0-∞)increased by about 205%). Total apparent oralclearance decreased by 70% with co-administration. Elimination half-lifecould not be estimated accurately as plasma concentrations were notquantifiable after 24 hours.

FIG. 4 shows a pharmacokinetic profile comparison of single-dosecolchicine (0.6 mg, alone) and single-dose colchicine (0.6 mg)co-administered with steady-state ritonavir and steady-stateketoconazole in healthy adults. Based on the foregoing data, the dose ofcolchicine co-administered with ketoconazole should be reduced byapproximately ½.

Example 6 Clinical Drug-Drug Interaction Study of Colchicine andAzithromycin

This study was an open-label, non-randomized, single-center,one-sequence, two-period drug interaction study conducted in healthymale and female volunteers; there was a 14-day washout between the twoperiods. Twenty-four (24) non-smoking, non-obese adult volunteers wereenrolled. All subjects were dosed and studied as a single cohort, witheach subject receiving the same treatment in a non-randomized fashion.

A single dose of colchicine, 0.6 mg, was administered alone on Day 1,and then co-administered with the azithromycin on Day 19. Azithromycinwas administered for 5 consecutive days (2×250 mg once daily [Day 15only] and then 1×250 mg once daily Days 16-19) beginning on the morningof Day 15, with the last 250 mg azithromycin dose administered on themorning on Day 19. Total study participation, exclusive of up to 28 daysof screening, was approximately 24 days, during which subjects wereconfined on two occasions for a total confinement of approximately 3days.

Serial blood samples were collected by individual venipuncture up to 96hours following drug administration on Day 1 and Day 19. Blood samplesfor determination of colchicine plasma concentrations were obtained attime zero (pre-dose) and after dose administration at 0.5, 1.0, 1.5, 2,3, 4, 5, 6, 8, 12, and 24 hours post-dose on an inpatient basis.Subjects returned to the clinic on an outpatient basis for continuedblood sampling collection at 36, 48, 72, and 96 hours post-doseadministration. Azithromycin plasma concentrations were not measured.

TABLE 12 Comparison of Single-Dose Colchicine (0.6 mg, Alone) andSingle-Dose Colchicine (0.6 mg) Co-Administered with Steady-StateAzithromycin in Healthy Adults Colchicine Colchicine + AloneAzithromycin % Ratio C_(max) (pg/mL), 2535.94 2856.22 112.63 geometricmean AUC_(0-t) (pg · hr/mL), 10971.51 16090.52 146.66 geometric meanAUC_(∞) (pg · hr/mL), 12931.80 18312.83 141.61 geometric mean

TABLE 13 Comparison of Single-Dose Colchicine (0.6 mg, Alone) andSingle-Dose Colchicine (0.6 mg) Co-Administered with Steady-StateAzithromycin in Healthy Adults Arithmetic Mean (% CV) Median (Range) forT_(max) Colchicine + Colchicine Azithromycin Alone Parameter (units) (N= 21) (N = 21) AUC_(0-t) (ng · hr/mL) 17.16 (37.78) 11.98 (45.81)AUC_(0-∞) (ng · hr/mL) 19.61 (39.15) 14.13 (46.73) C_(max) (ng/mL) 3.05(39.54) 2.74 (41.52) T_(max) (hr) 1.5 (0.5-3) 1.0 (0.5-3) t_(1/2) (hr)6.71 (68.34)¹ 6.07 (66.15)¹ CL/F (L/hr) 35.01 (37.26) 50.24 (40.31)

Following administration of azithromycin 500 mg on Day 1 followed by 250mg×4 days, exposure to colchicine is increased (approximately 46% forAUC_(0-t) and approximately 40% for AUC_(0-∞)). Mean peak colchicineconcentration increased by approximately 12% and total apparent oralclearance decreased approximately 30% with co-administration. T_(max)was not affected.

FIG. 5 shows a pharmacokinetic profile comparison of single-dosecolchicine (0.6 mg, alone) and single-dose colchicine (0.6 mg)co-administered with steady-state azithromycin and steady-statediltiazem in healthy adults.

Example 7 Clinical Drug-Drug Interaction study of Colchicine andDiltiazem

This study was an open-label, non-randomized, single-center,one-sequence, two-period drug interaction study conducted in healthymale and female volunteers. Twenty-four (24) non-smoking, non-obeseadult volunteers were enrolled. All subjects were dosed and studied as asingle cohort, with each subject receiving the same treatment in anon-randomized fashion.

As single dose of colchicine, 0.6 mg, was administered alone on Day 1,and then co-administered with diltiazem ER on Day 21. Diltiazem ER wasadministered for 7 consecutive days (1×240 mg capsule once daily on Days15-21) beginning on the morning of Day 15, with the last 240 mgdiltiazem ER dose administered on the morning on Day 21. A 14-daywashout period was completed after the first colchicine dose on Day 1and prior to the administration of the first diltiazem ER dose on Day15.

Serial blood samples were collected by individual venipuncture up to 96hours following drug administration on Day 1 and Day 21. Blood samplesfor determination of colchicine plasma concentrations were obtained attime zero (pre-dose) and after dose administration at 0.5, 1.0, 1.5, 2,3, 4, 5, 6, 8, 12, and 24 hours post-dose on an inpatient basis.Subjects returned to the clinic on an outpatient basis for continuedblood sampling collection at 36, 48, 72, and 96 hours post-doseadministration. Diltiazem plasma concentrations were not measured.

TABLE 14 Comparison of Single-Dose Colchicine (0.6 mg, Alone) andSingle-Dose Colchicine (0.6 mg) Co-Administered with Steady-StateDiltiazem in Healthy Adults Colchicine Colchicine + Alone Diltiazem %Ratio C_(max) (pg/mL), 2006.42 2583.22 128.75 geometric mean AUC_(0-t)(pg · h/mL), 9154.55 15740.37 171.94 geometric mean AUC_(∞) (pg · h/mL),11022.30 19902.98 180.57 geometric mean

TABLE 15 Comparison of Single-Dose Colchicine (0.6 mg, Alone) andSingle-Dose Colchicine (0.6 mg) Co-Administered with Steady-StateDiltiazem in Healthy Adults Arithmetic Mean (% CV) Median (Range) forT_(max) Colchicine + Colchicine Diltiazem Alone Parameter (units) (N =20) (N = 20) AUC_(0-t) (ng · hr/mL) 17.73 10.04 AUC_(0-∞) (ng · hr/mL)22.49 12.03 C_(max) (ng/mL) 2.80 2.17 T_(max) (hr) 1.48 1.15 t_(1/2)(hr) 12.50 5.51 CL/F (L/hr) 463.49 395.83

FIG. 5 shows a pharmacokinetic profile comparison of single-dosecolchicine (0.6 mg, alone) and single-dose colchicine (0.6 mg)co-administered with steady-state azithromycin and steady-statediltiazem in healthy adults.

Example 8 Clinical Drug-Drug Interaction Study of Colchicine andVerapamil

This study was an open-label, non-randomized, single-center,one-sequence, two-period drug interaction study conducted in healthymale and female volunteers. Twenty-four (24) non-smoking, non-obeseadult volunteers were enrolled. All subjects were dosed and studied as asingle cohort, with each subject receiving the same treatment in anon-randomized fashion.

A single dose of colchicine, 0.6 mg, was administered alone on Day 1,and then co-administered with verapamil HCl ER on Day 19. Verapamil HClER was administered for 5 consecutive days (1×240 mg tablet once dailyon Days 15-19) beginning on the morning of Day 15, with the last 240 mgverapamil HCl ER dose administered on the morning on Day 19. A 14-daywashout period was completed after the first colchicine dose on Day 1and prior to the administration of the first verapamil HCL ER dose onDay 15.

Serial blood samples were collected by individual venipuncture up to 96hours following drug administration on Day 1 and Day 19. Blood samplesfor determination of colchicine plasma concentrations were obtained attime zero (pre-dose) and after dose administration at 0.5, 1.0, 1.5, 2,3, 4, 5, 6, 8, 12, and 24 hours post-dose on a confined basis. Subjectsreturned to the clinic on a non-confined basis for continued bloodsampling collection at 36, 48, 72, and 96 hours post-dose administrationon Days 2-5 (Period 1) and Days 20-23 (Period 2). Verapamil plasmaconcentrations were not measured.

TABLE 16 Comparison of Single-Dose Colchicine (0.6 mg, Alone) andSingle-Dose Colchicine (0.6 mg) Co-Administered with Steady-StateVerapamil in Healthy Adults Colchicine Colchicine + Alone Verapamil %Ratio C_(max) (pg/mL), 2768.77 3639.68 131.45 geometric mean AUC_(0-t)(pg · h/mL), 12256.40 23889.21 194.94 geometric mean AUC_(∞) (pg ·h/mL), 14415.79 29556.75 205.03 geometric mean

TABLE 17 Comparison of Single-Dose Colchicine (0.6 mg, Alone) andSingle-Dose Colchicine (0.6 mg) Co-Administered with Steady-StateVerapamil in Healthy Adults Arithmetic Mean (% CV) Median (Range) forT_(max) Colchicine + Colchicine Verapamil Alone Parameter (units) (N =24) (N = 24) AUC_(0-t) (ng · hr/mL) 24.64 13.09 AUC_(0-∞) (ng · hr/mL)30.59 15.37 C_(max) (ng/mL) 3.85 2.97 T_(max) (hr) 1.15 1.22 t_(1/2)(hr) 17.17 6.24 CL/F (L/hr) 21.01 43.93

Recitation of ranges of values herein are merely intended to serve as ashorthand method of referring individually to each separate valuefalling within the range, unless otherwise indicated herein, and eachseparate value is incorporated into the specification as if it wereindividually recited herein. The endpoints of all ranges directed to thesame component or property are inclusive and independently combinable.

All methods described herein can be performed in a suitable order unlessotherwise indicated or clearly contradicted by context. The use of anyand all examples, or exemplary language (e.g., “such as”) herein isintended to better illuminate the disclosure and is non-limiting unlessotherwise specified. No language in the specification should beconstrued as indicating that any non-claimed element as essential to thepractice of the claimed embodiments. Unless defined otherwise, technicaland scientific terms used herein have the same meaning as is commonlyunderstood by one of skill in the art to which this disclosure belongs.The terms wt %, weight percent, percent by weight, etc. are equivalentand interchangeable.

In the specification and claims that follow, references will be made toa number of terms which shall be defined to have the following meaning.

The terms “a” and “an” do not denote a limitation of quantity, butrather denote the presence of at least one of the referenced item. Theterm “or” means “and/or”. The terms “comprising”, “having”, “including”,and “containing” are to be construed as open-ended terms (i.e., meaning“including, but not limited to”).

“Concomitant” and “concomitantly” as used herein refer to theadministration of at least two drugs to a patient either simultaneouslyor within a time period during which the effects of the firstadministered drug are still operative in the patient. Thus, if the firstdrug is, e.g., clarithromycin and the second drug is colchicine, theconcomitant administration of the second drug can occur as much as oneto two weeks, preferably within one to seven days, after theadministration of the first drug. This is because clarithromycin canexert a long-lasting inhibition of CYP3A isozymes so that CYP3A activityin the patient may not return to pre-clarithromycin-administrationlevels for as much as two weeks after the cessation of clarithromycinadministration. If colchicine is the first drug, administration of asecond drug would be concomitant if done within 1 to 2 days, preferably12 to 24 hours.

A “dose” means the measured quantity of a drug to be taken at one timeby a patient.

A “dosage amount” means an amount of a drug suitable to be taken duringa fixed period, usually during one day (i.e. daily). A “daily dosageamount” is the total dosage amount taken in one day, that is, a 24 hourperiod.

“Dosing regimen” means the dose of a drug taken at a first time by apatient and the interval (time or symptomatic) and dosage amounts atwhich any subsequent doses of the drug are taken by the patient. Eachdose may be of the same or different.

A “patient” means a human or non-human animal in need of medicaltreatment. Medical treatment can include treatment of an existingcondition, such as a disease or disorder, prophylactic or preventativetreatment, or diagnostic treatment. In preferred embodiments the patientis human.

“Providing” means giving, administering, selling, distributing,transferring (for profit or not), manufacturing, compounding, ordispensing.

“Risk” means the probability or chance of adverse reaction, injury, orother undesirable outcome arising from a medical treatment. An“acceptable risk” means a measure of the risk of harm, injury, ordisease arising from a medical treatment that will be tolerated by anindividual or group. Whether a risk is “acceptable” will depend upon theadvantages that the individual or group perceives to be obtainable inreturn for taking the risk, whether they accept whatever scientific andother advice is offered about the magnitude of the risk, and numerousother factors, both political and social. An “acceptable risk” of anadverse reaction means that an individual or a group in society iswilling to take or be subjected to the risk that the adverse reactionmight occur since the adverse reaction is one whose probability ofoccurrence is small, or whose consequences are so slight, or thebenefits (perceived or real) of the active agent are so great. An“unacceptable risk” of an adverse reaction means that an individual or agroup in society is unwilling to take or be subjected to the risk thatthe adverse reaction might occur upon weighing the probability ofoccurrence of the adverse reaction, the consequences of the adversereaction, and the benefits (perceived or real) of the active agent. “Atrisk” means in a state or condition marked by a high level of risk orsusceptibility.

Pharmacokinetic parameters referred to herein describe the in vivocharacteristics of drug (or a metabolite or a surrogate marker for thedrug) over time. These include plasma concentration (C), as well asC_(max), C_(n), C₂₄, T_(max), and AUC. “C_(max)” is the measured plasmaconcentration of the active agent at the point of maximum, or peak,concentration. “C_(min)” is the measured plasma concentration of theactive agent at the point of minimum concentration. “C_(n)” is themeasured plasma concentration of the active agent at about n hours afteradministration. “C₂₄” is the measured plasma concentration of the activeagent at about 24 hours after administration. The term “T_(max)” refersto the time from drug administration until C_(max) is reached. “AUC” isthe area under the curve of a graph of the measured plasma concentrationof an active agent vs. time, measured from one time point to anothertime point. For example AUC_(0-t) is the area under the curve of plasmaconcentration versus time from time 0 to time t, where time 0 is thetime of initial administration of the drug. Time t can be the last timepoint with measurable plasma concentration for an individualformulation. The AUC_(0-∞), AUC_(∞) or AUC_(0-inf) is the calculatedarea under the curve of plasma concentration versus time from time 0 totime infinity. In steady-state studies, AUC_(0-τ) is the area under thecurve of plasma concentration over the dosing interval (i.e., from time0 to time τ (tau), where tau is the length of the dosing interval. Otherpharmacokinetic parameters are the parameter K_(e) or K_(d), theterminal elimination rate constant calculated from a semi-log plot ofthe plasma concentration versus time curve; t_(1/2) the terminalelimination half-life, calculated as 0.693/K_(el). CL/F denotes theapparent total body clearance after administration, calculated as TotalDose/Total AUC_(∞); and V_(area)/F denotes the apparent total volume ofdistribution after administration, calculated as Total Dose/(TotalAUC_(∞)×K_(el)).

“Side effect” means a secondary effect resulting from taking a drug. Thesecondary effect can be a negative (unfavorable) effect (i.e., anadverse side effect) or a positive (favorable) effect.

The most frequently reported adverse side effects to colchicine therapyare gastrointestinal, specifically abdominal pain with cramps, diarrhea,nausea, and vomiting. Less frequently or rarely reported adverse sideeffects associated with colchicine therapy include anorexia,agranulocytosis, allergic dermatitis, allergic reactions, alopecia,angioedema, aplastic anemia, bone marrow depression, myopathy,neuropathy, skin rash, thrombocytopenic disorder, and urticaria.

Whether a patient experiences an adverse side effect can be determinedby obtaining information from the patient regarding onset of certainsymptoms which may be indicative of the adverse side effect, results ofdiagnostic tests indicative of the adverse side effect, and the like.

Embodiments are described herein, including the best modes known to theinventors. Variations of such embodiments will become apparent to thoseof ordinary skill in the art upon reading the foregoing description. Theskilled artisan is expected to employ such variations as appropriate,and the disclosed methods are expected to be practiced otherwise than asspecifically described herein. Accordingly, all modifications andequivalents of the subject matter recited in the claims appended heretoare included to the extent permitted by applicable law. Moreover, anycombination of the above-described elements in all possible variationsthereof is encompassed unless otherwise indicated herein or otherwiseclearly contradicted by context.

1. A method of treating a patient with colchicine, comprising orally administering an adjusted daily dosage amount of colchicine to the patient who is receiving concomitant administration of ketoconazole, wherein the adjusted daily dosage amount of colchicine is 25% to 50% of an intended daily dosage amount of colchicine, and wherein the intended daily dosage amount of colchicine is a dosage amount suitable for the patient if the patient were not receiving concomitant ketoconazole.
 2. The method of claim 1, wherein the treating is for the prophylaxis of gout flares, and wherein the intended daily dosage amount of colchicine suitable for the patient if the patient were not receiving concomitant ketoconazole is 0.6 mg twice daily or 0.6 mg once daily.
 3. The method of claim 1, wherein the treating is for acute gout flares, and wherein the intended daily dosage amount of colchicine suitable for the patient if the patient were not receiving concomitant ketoconazole is 1.2 mg at the first sign of flare, followed by 0.6 mg one hour later, dose to be repeated no earlier than 3 days.
 4. The method of claim 1, wherein the treating is for familial Mediterranean fever wherein the adjusted daily dosage amount of colchicine is a maximum colchicine dosage amount of 0.6 mg of colchicine per day which is a reduction from the intended daily dosage amount of colchicine in the absence of concomitant ketoconazole wherein the intended daily dosage amount is a maximum daily dosage amount as follows: Daily dosage amount Age Usual Maximum Adults and children >12 years 1.2 mg 2.4 mg Children >6 to 12 years 0.9 mg 1.8 mg Children 4 to 6 years 0.3 mg  1.8 mg.


5. The method of claim 2, wherein the adjusted daily dosage amount of colchicine is 25% of a 0.6 mg twice daily intended dose.
 6. The method of claim 2, wherein the adjusted daily dosage amount of colchicine is 25% of a 0.6 mg once daily intended dose.
 7. The method of claim 1, wherein the concomitantly administered dose of ketoconazole is 200 mg twice per day.
 8. The method of claim 3, wherein the adjusted daily dosage amount is about 50% of the intended daily dosage amount. 